Optimizing ImmunotherapyNew approached, biomarkers, sequences and

combinations

Joaquim Bellmunt, MD PhD

Director. Hospital del Mar Medical Research Institute (IMIM)

Associate Professor of MedicineHarvard Medical School/Dana‐Farber Cancer Institute

Barcelona, Oct 20th 2017

Disclosures

• Advisory role: ◦ Genentech, Merck, Pfizer, GSK, BMS, Pierre-Fabre, Sanofi Aventis,

Astellas, OncoGenex, Janssen

• Speaker role: ◦ Pfizer, Merck, GSK, Novartis, Pierre-Fabre, Astellas

• Research funding:◦ Takeda, Pfizer, Novartis, Sanofi Aventis

• 1796 First use of immunotherapy to control disease – smallpox vaccine• 1975 First production of monoclonal antibodies for therapeutic use• 1986 IFN‐alpha: First immuno‐oncology treatment approved for cancer 

(hairy cell leukemia)• 1990 Bacillus Calmette‐Guerin (BCG) (bladder cancer)• 2010 Sipuleucel‐T (prostate cancer)• 2011 CTLA‐4 inhibitor ipilimumab (metastatic melanoma)• 2014 Blinatumomab (acute lymphoblastic leukemia)• 2014 Anti‐PD‐1 monoclonal antibodies pembrolizumab and nivolumab

(unresectable or metastatic melanoma)

• 2015 Adjuvant ipilimumab (melanoma)• 2015‐16  Nivolumab, pembrolizumab (NSCLC, RCC)• 2016‐17 Nivolumab, atezolizumab, durvalumab,Avelumab, pembrolizumab

approved in several  tumor types• 2017‐ CAR‐T cells approved for ALL and refractory adult large B‐cell 

lymphoma

A Brief History of Immuno‐Oncology

Genetic Basis For Clinical Response• Is there a role for mutational frequency in tumor selection

for PD1/PD-L1 pathway inhibition?

Many tumors that respond to PD1 pathway inhibition: Melanoma, NSCLC, and Bladder Cancer have a high mutation rate

Current US/EU Approval Status of Immune Checkpoint Inhibitors

US EU

PD‐1 PD‐L1 CTLA‐4

Combo

Pembrolizumab Nivolumab Atezolizumab Durvalumab Avelumab Ipilimumab

Nivo + ipi

Line 1L+ 2L+ 3L+ 1L+ 2L+ 3L+ 1L+** 2L+ 2L+ 1L+ 2L+ 1L+ 1L+

mMelanoma

Lung Hodgkin

aRCC mHNSCC

mUC

Merkel cell

NEW

EU, European Union; HNSCC, head and neck squamous cell carcinoma; ipi, ipilimumab; m, metastatic; nivo, nivolumab; PD‐1, programmed cell death protein‐1; PD‐L1, programmed death‐ligand 1; RCC, renal cell carcinoma; UC, urothelial carcinoma; US, United States.Product Prescribing Information.

Pembrolizumab indicated for treatment of patientswith unresectable / metastatic solid tumors that aremicrosatellite instability-high (MSI-H) or mismatchrepair deficient (dMMR)

FDA, May 23rd , 2017

Gay N, Prasad V. STAT. March 8, 2017. https://www.statnews.com/2017/03/08/immunotherapy‐cancer‐breakthrough/..

Cancer patients’ response to an immunotherapy drug 

Any Response No Response

Checkpoint inhibitor for cancers approved for immunotherapy

Checkpoint inhibitor for any type of cancer

Response Rate (%)

0

Cancer Patients’ Response to an IO Drug

25 50 75 100

Potential Biomarkers for PD‐1/PD‐L1 therapy

• PD-L1 by IHQ. CD8 infiltrate.

• RNA immune signatures

• Neoantigen and mutational burden (MSI,defects in DNA repair)

• T cell clonality. genetically amplified PD=L1 and PD-L2

(Hodgkin),Viral antigens (HPV, Head and neck, Merkel)

• Other mutations and CNV

Understanding immunology and genetics  has identified groups that respond well to PD‐1/PD‐L1 therapy

• PD-L1: the antibody, cut off points, disease and timing matters

• RNA immune signatures and T cell clonality emerging. RNA subtypes to be confirmed

• Highly mutated tumors (MSI, defects in DNA repair -DDR genes-)

• Neoantigen and mutational burden to be confirmed in select tumors

Response enrichment with all these biomarkers

• Dynamic markers, recent tissue better

• Different in combination trials

• Genetically amplified PD=L1 and PD-L2 (Hodgkin),Viral antigens (HPV, Head and neck,

Merkel)

• More biomarkers to come …….!!!!!

Can We Select Patients More Likely to Respond to PD‐1/L1 Blockade?

1. Pre‐existing T cell infiltration and adaptive PD‐L1 expression

Tumeh, et al. Nature. 2014.

Herbst, et al. Nature. 2014.

2. TCR clonality

Tumeh, et al. Nature. 2014.

3. IFN signature by expression profiling

NonresponderResponder0.81.01.21.41.61.82.02.22.4

Best Overall Response,  RECISTv1.1

Ribas, et al. ASCO. 2015.

4. Mutational load

Le, et al. NEJM. 2015.

Rizvi, et al. Science. 2015.

5. Transcriptome

Hugo, et al. Cell. 2016.

Immunotherapy Today• Exciting times in the treatment of cancer• Immunotherapy is a well tolerated and active treatment for our 

patients• Many open questions remain with regards to understanding 

predicting factors• Several other novel immunotherapies are in clinical development

– New Checkpoint inhibitors– Combinations (IO/Chemo)– Antibody drug conjugates– Targeted agents

• Chemotherapy is here to stay

Immunotherapy in UC

• Exciting times in the treatment of cancer

• Immunotherapy is a well tolerated and active treatment for our patients

• But only 15-20% of patients derive benefit and many open questions remain with regards to understanding predicting factors

• The future is combination (or sequential ?)◦ Check-point inhibitors◦ Immune based therapies (vaccines, ADC, Bispecific antibodies,

CAR-T cells…) ◦ + Targeted agents (cabozantinib, FGFr3 inh..)◦ Combination/ Sequential use of chemo and XRT◦ Customized: Genomically based